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PubMed This is a summary of 13 peer-reviewed journal articles Updated
Medical Genetics

The Biology of Abetalipoproteinemia: A "Shipping" Failure

At a Glance

Abetalipoproteinemia results from MTTP variants that prevent the body from building fat-carrying particles. This causes very low cholesterol and fat levels in the blood and deficiencies of vitamins A, D, E, and K; genetic testing helps distinguish ABL from similar disorders.

To understand abetalipoproteinemia (ABL), it helps to think of your body as a shipping center that has lost its ability to package and send out vital supplies. This rare condition is caused by a pathogenic variant (mutation) in the MTTP gene, which provides the instructions for making the microsomal triglyceride transfer protein (MTP) [1][2].

The Role of the MTP Protein

The MTP protein is a critical worker found in the cells of your liver and small intestine. Its primary job is to help build lipoproteins, which are the “shipping containers” your body uses to move fats and vitamins through your bloodstream [1].

Specifically, MTP takes a protein called apolipoprotein B (apoB) and loads it with fats like triglycerides and phospholipids [2][3]. This process creates two main types of containers:

  • Chylomicrons: These are made in the intestine to transport fats and vitamins from your food into the body [1].
  • VLDL (Very Low-Density Lipoprotein): These are made in the liver to distribute stored fats to the rest of the body [1].

In someone with ABL, the MTP protein is either missing or doesn’t work correctly. Because these “containers” are severely impaired in being built, fats and vitamins A, D, E, and K accumulate inside the intestinal cells and the liver instead of properly reaching your blood [4][2]. This leads to the very low cholesterol levels and severe vitamin deficiencies characteristic of the condition [5].

Why Vitamin Deficiency Happens

Since vitamins A, D, E, and K are “fat-soluble,” they generally hitch a ride on those fat-filled chylomicrons to enter the body from the gut [4]. Without enough of these transport ships, the body’s natural absorption of these nutrients is markedly reduced. This is why patients with ABL require specialized, high-dose or water-miscible vitamin therapy that can find other ways into the bloodstream [5][6].

Telling ABL Apart from Similar Conditions

Several other rare genetic conditions can cause extremely low cholesterol and similar digestive issues. Doctors use a differential diagnosis—a process of distinguishing between similar conditions—to find the exact cause, though molecular testing is crucial.

Condition Genetic Cause What’s Missing? Unique Features
Abetalipoproteinemia (ABL) MTTP gene No apoB-48 (gut) or apoB-100 (liver) [4]. Very low lipids in both the gut and liver; parents usually have normal cholesterol [5].
Homozygous Familial Hypobetalipoproteinemia (HoFHBL) APOB gene Missing or broken apoB proteins [4]. Often looks identical to ABL, but parents typically have very low cholesterol too [7][8].
Chylomicron Retention Disease (Anderson Disease) SAR1B gene Defective “shipping docks” in the gut [9]. Hepatic VLDL production is relatively preserved, but fat-soluble-vitamin deficiency can still produce systemic consequences. Only apoB-48 (the gut container) is primarily affected [10].

While ABL and HoFHBL affect both the liver and the gut, Chylomicron Retention Disease has differing biological mechanisms [4][9]. Genetic testing is the most reliable way to help tell these conditions apart [11][12]. However, a negative genetic panel does not always perfectly exclude ABL, as complex variants or “variants of uncertain significance” can occur. It is highly recommended to consult a certified genetic counselor for family testing, carrier testing, and reproductive planning, rather than relying solely on checking parents’ cholesterol levels to confirm or exclude the diagnosis [7][13].

Common questions in this guide

What causes abetalipoproteinemia?
Abetalipoproteinemia is caused by disease-causing variants in the MTTP gene. These variants impair microsomal triglyceride transfer protein, so the intestine and liver cannot properly build the fat-carrying particles needed to transport fats and vitamins.
Why are vitamins A, D, E, and K low in ABL?
These vitamins are fat-soluble, so they normally enter the body in fat-carrying particles made in the intestine. When ABL disrupts those particles, absorption and delivery of the vitamins fall, which is why specialized high-dose or water-miscible vitamin therapy may be needed.
How does ABL differ from homozygous familial hypobetalipoproteinemia?
ABL is linked to MTTP variants, while homozygous familial hypobetalipoproteinemia, or HoFHBL, is linked to APOB variants. The two can look very similar, but parents in a family with ABL often have normal cholesterol, whereas parents in familial hypobetalipoproteinemia often have very low cholesterol; genetic testing is more reliable than this pattern alone.
How is ABL different from chylomicron retention disease?
ABL results from MTTP variants and affects lipoprotein formation in both the intestine and liver. Chylomicron retention disease is linked to SAR1B and primarily disrupts intestinal chylomicron handling while liver VLDL production is relatively preserved. Genetic testing helps distinguish them.
Can a negative genetic test rule out abetalipoproteinemia?
No. A negative panel may not detect complex MTTP variants, and a variant of uncertain significance does not by itself establish the diagnosis. A certified genetic counselor can help interpret the result and decide whether additional testing or family testing is appropriate.
What symptoms might suggest vitamin deficiency in ABL?
Digestive symptoms may occur, and vitamin deficiency can be associated with problems such as night blindness or poor balance. These symptoms can have other causes, so a healthcare professional should evaluate them rather than using symptoms alone to diagnose ABL.
Should relatives be checked for abetalipoproteinemia?
Because ABL is caused by an MTTP gene variant, a genetic counselor can advise whether parents, siblings, or other relatives should have genetic or carrier testing. Cholesterol testing may provide clues, but checking a relative's cholesterol alone cannot confirm or exclude the diagnosis; counseling can also support reproductive planning.

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References

References (13)
  1. 1

    Lipid transfer proteins in the assembly of apoB-containing lipoproteins.

    Sirwi A, Hussain MM

    Journal of lipid research 2018; (59(7)):1094-1102 doi:10.1194/jlr.R083451.

    PMID: 29650752
  2. 2

    Generation of hepatoma cell lines deficient in microsomal triglyceride transfer protein.

    Anaganti N, Chattopadhyay A, Poirier JT, Hussain MM

    Journal of lipid research 2022; (63(9)):100257 doi:10.1016/j.jlr.2022.100257.

    PMID: 35931202
  3. 3

    The crystal structure of human microsomal triglyceride transfer protein.

    Biterova EI, Isupov MN, Keegan RM, et al.

    Proceedings of the National Academy of Sciences of the United States of America 2019; (116(35)):17251-17260 doi:10.1073/pnas.1903029116.

    PMID: 31395737
  4. 4

    Forty year follow-up of three patients with complete absence of apolipoprotein B-containing lipoproteins.

    Le R, Zhao L, Hegele RA

    Journal of clinical lipidology 2022; (16(2)):155-159 doi:10.1016/j.jacl.2022.02.003.

    PMID: 35221233
  5. 5

    Current Diagnosis and Management of Abetalipoproteinemia.

    Takahashi M, Okazaki H, Ohashi K, et al.

    Journal of atherosclerosis and thrombosis 2021; (28(10)):1009-1019 doi:10.5551/jat.RV17056.

    PMID: 33994405
  6. 6

    Abetalipoproteinemia Due to a Novel Splicing Variant in MTTP in 3 Siblings.

    Vlasschaert C, McIntyre AD, Thomson LA, et al.

    Journal of investigative medicine high impact case reports 2021; (9()):23247096211022484 doi:10.1177/23247096211022484.

    PMID: 34078172
  7. 7

    Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1.

    Wakabayashi T, Takahashi M, Okazaki H, et al.

    Journal of atherosclerosis and thrombosis 2024; (31(7)):1005-1023 doi:10.5551/jat.RV22018.

    PMID: 38710625
  8. 8

    The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations.

    Di Leo E, Eminoglu T, Magnolo L, et al.

    Journal of clinical lipidology 2015; (9(3)):400-5.

    PMID: 26073401
  9. 9

    Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.

    Auclair N, Sané AT, Ahmarani L, et al.

    Journal of lipid research 2021; (62()):100085 doi:10.1016/j.jlr.2021.100085.

    PMID: 33964306
  10. 10

    Low cholesterol states: clinical implications and management.

    Gill PK, Hegele RA

    Expert review of endocrinology & metabolism 2023; (18(3)):241-253 doi:10.1080/17446651.2023.2204932.

    PMID: 37089071
  11. 11

    Lipids Responsible for Intestinal or Hepatic Disorder: When to Suspect a Familial Intestinal Hypocholesterolemia?

    Sissaoui S, Cochet M, Poinsot P, et al.

    Journal of pediatric gastroenterology and nutrition 2021; (73(1)):4-8 doi:10.1097/MPG.0000000000003145.

    PMID: 33853111
  12. 12

    Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B.

    Yilmaz BS, Mungan NO, Di Leo E, et al.

    Clinica chimica acta; international journal of clinical chemistry 2016; (452()):185-90.

    PMID: 26612772
  13. 13

    Novel mutations of SAR1B gene in four children with chylomicron retention disease.

    Simone ML, Rabacchi C, Kuloglu Z, et al.

    Journal of clinical lipidology 2019; (13(4)):554-562 doi:10.1016/j.jacl.2019.05.013.

    PMID: 31253576

This page explains how MTTP variants affect fat and vitamin transport for informational purposes only and does not constitute medical advice. Ask a genetic counselor or healthcare professional to interpret your results and discuss care.

Guide contents Abetalipoproteinemia
Research & Literature
02 Recognizing and Monitoring Symptoms of Abetalipoproteinemia (ABL) 04 Diagnosing ABL